Anisotropic Effect Size-signed Differential Mapping Research Articles

Grey matter structural alterations in anxiety disorders: a voxel-based meta-analysis.

Anxiety disorders (ADs) are a group of prevalent and destructive mental illnesses, but the current understanding of their underlying neuropathology is still unclear. Employing voxel-based morphometry (VBM), previous studies have demonstrated several common brain regions showing grey matter volume (GMV) abnormalities. However, contradictory results have been reported among these studies. Considering that different subtypes of ADs exhibit common core symptoms despite different diagnostic criteria, and previous meta-analyses have found common core GMV-altered brain regions in ADs, the present research aimed to combine the results of individual studies to identify common GMV abnormalities in ADs. Therefore, we first performed a systematic search in PubMed, Embase, and Web of Science on studies investigating GMV differences between patients with ADs and healthy controls (HCs). Then, the anisotropic effect-size signed differential mapping (AES-SDM) was applied in this meta-analysis.A total of 24 studies (including 25 data sets) were included in the current study, and 906 patients with ADs and 1003 HCs were included. Compared with the HCs, the patients with ADs showed increased GMV in the left superior parietal gyrus, right angular gyrus, left precentral gyrus, and right lingual gyrus, and decreased GMV in the bilateral insula, bilateral thalamus, left caudate, and right putamen. In conclusion,the current study has identified some abnormal GMV brain regions that are related to the pathological mechanisms of anxiety disorders. These findings could contribute to a better understanding of the underlying neuropathology of ADs.

Shared and distinct abnormalities of brain magnetization transfer ratio in schizophrenia and major depressive disorder: a comparative voxel-based meta-analysis.

Patients with schizophrenia (SCZ) and major depressive disorder (MDD) share significant clinical overlap, although it remains unknown to what extent this overlap reflects shared neural profiles. To identify the shared and specific abnormalities in SCZ and MDD, we performed a whole-brain voxel-based meta-analysis using magnetization transfer imaging, a technique that characterizes the macromolecular structural integrity of brain tissue in terms of the magnetization transfer ratio (MTR). A systematic search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in PubMed, EMBASE, International Scientific Index (ISI) Web of Science, and MEDLINE for relevant studies up to March 2022. Two researchers independently screened the articles. Rigorous scrutiny and data extraction were performed for the studies that met the inclusion criteria. Voxel-wise meta-analyses were conducted using anisotropic effect size-signed differential mapping with a unified template. Meta-regression was used to explore the potential effects of demographic and clinical characteristics. A total of 15 studies with 17 datasets describing 365 SCZ patients, 224 MDD patients, and 550 healthy controls (HCs) were identified. The conjunction analysis showed that both disorders shared higher MTR than HC in the left cerebellum ( P =0.0006) and left fusiform gyrus ( P =0.0004). Additionally, SCZ patients showed disorder-specific lower MTR in the anterior cingulate/paracingulate gyrus, right superior temporal gyrus, and right superior frontal gyrus, and higher MTR in the left thalamus, precuneus/cuneus, posterior cingulate gyrus, and paracentral lobule; and MDD patients showed higher MTR in the left middle occipital region. Meta-regression showed no statistical significance in either group. The results revealed a structural neural basis shared between SCZ and MDD patients, emphasizing the importance of shared neural substrates across psychopathology. Meanwhile, distinct disease-specific characteristics could have implications for future differential diagnosis and targeted treatment.

A meta-analysis of brain morphometric aberrations in adolescents who experienced childhood trauma.

Childhood trauma is known to have dramatic effects on the risks for developing psychiatric disorders and increased suicidality. We conducted a meta-analysis of whole brain voxel-based morphometry (VBM) correlates of childhood trauma in adolescents exposed to childhood maltreatment (N = 379) and unexposed controls (N = 348). Anisotropic effect size-signed differential mapping (AES-SDM) was utilized to synthesize the studies. We observed increased volume amongst adolescents with a history of childhood trauma in regions that are involved in motor functions and language production: left precentral gyrus, including part of the left inferior frontal gyrus, left fibers of the body of corpus callosum, and left postcentral gyrus. We observed decreased volume amongst adolescents with a history of childhood trauma in regions that are involved in language processing and/or sensory processing: bilateral cerebellum, bilateral middle temporal gyrus, left rostrum of corpus callosum, and bilateral supramarginal gyrus. We suggest that these morphometric differences may be reflective of impaired motor development and increased sensory sensitivity and hypervigilance in adolescents with experiences of childhood trauma. Our results differ from meta-analytical findings in adults with history of childhood trauma and may contribute to a better understanding of neural mechanisms of childhood trauma, prediction of neurodevelopmental outcomes, and development of more effective and personalized therapies.

A systematic review and meta-analysis of voxel-based morphometric studies of migraine.

To comprehensively summarize and meta-analyze the concurrence across voxel-based morphometric (VBM) neuroimaging studies of migraine. Neuroimaging studies published from origin to August 1, 2021 were searched in six databases including PubMed, Web of Science, Excerpta Medica Database (EMBASE), China National Knowledge Infrastructure (CNKI), Wanfang Database, and Chongqing VIP. Study selection, quality assessment, and data extraction were conducted by two independent researchers. Anisotropic effect size-signed differential mapping (AES-SDM) and activation likelihood estimation (ALE) were used to perform the meta-analysis of available studies reporting whole-brain gray matter (GM) structural data in migraine patients. Clinical variables correlation analysis and migraine subgroup analysis were also conducted. 40 articles were included after the strict screening, containing 1616 migraine patients and 1681 matched healthy subjects (HS) in total. Using the method of AES-SDM, migraine patients showed GM increase in the bilateral amygdala, the bilateral parahippocampus, the bilateral temporal poles, the bilateral superior temporal gyri, the left hippocampus, the right superior frontal gyrus, and the left middle temporal gyrus, as well as GM decrease in the left insula, the bilateral cerebellum (hemispheric lobule IX), the right dorsal medulla, the bilateral rolandic operculum, the right middle frontal gyrus, and the right inferior parietal gyrus. Using the method of ALE, migraine patients showed GM increase in the left parahippocampus and GM decrease in the left insula. The results of correlation analysis showed that many of these brain regions were associated with migraine headache frequency and migraine disease duration. Migraine patients in different subtypes (such as migraine without aura (MwoA), migraine with aura (MwA), episodic migraine (EM), chronic migraine (CM), vestibular migraine (VM), etc.), and in different periods (in the ictal and interictal periods) presented not entirely consistent GM alterations. Migraine patients have GM alterations in multiple brain regions associated with sensation, affection, cognition, and descending modulation aspects of pain. These changes might be a consequence of repeated migraine attacks. Further studies are required to determine how these GM changes can be used to diagnose, monitor disease progression, or exploit potential therapeutic interventions for migraine patients.

Gray Matter Abnormalities in Patients with Complex Regional Pain Syndrome: A Systematic Review and Meta-Analysis of Voxel-Based Morphometry Studies.

Current findings on brain structural alterations in complex regional pain syndrome (CRPS) are heterogenous and controversial. This study aimed to perform a systematic review and meta-analysis to explore the significant gray matter volume (GMV) abnormalities between patients with CRPS and healthy controls (HCs). A systematic search of the PubMed, Web of Science, and MEDLINE databases was performed, updated through 27 January 2022. A total of five studies (93 CRPS patients and 106 HCs) were included. Peak coordinates and effect sizes were extracted and meta-analyzed by anisotropic effect size–signed differential mapping (AES-SDM). Heterogeneity, sensitivity, and publication bias of the main results were checked by the Q test, jackknife analysis, and the Egger test, respectively. Meta-regression analysis was performed to explore the potential impact of risk factors on GMV alterations in patients with CRPS. The main analysis exhibited that patients with CRPS had increased GMV in the left medial superior frontal gyrus (SFGmedial.L), left striatum, and an undefined area (2, 0, −8) that may be in hypothalamus, as well as decreased GMV in the corpus callosum (CC) (extending to right supplementary motor area (SMA.R), right median cingulate/paracingulate gyri (MCC.R)), and an undefined area (extending to the right caudate nucleus (CAU.R), and right thalamus (THA.R)). Meta-regression analysis showed a negative relationship between increased GMV in the SFGmedial.L and disease duration, and the percentage of female patients with CRPS. Brain structure abnormalities in the sensorimotor regions (e.g., SFGmedial.L, SMA.R, CAU.R, MCC.R, and THA.R) may be susceptible in patients with CRPS. Additionally, sex differences and disease duration may have a negative effect on the increased GMV in SFGmedial.L.

Abnormal resting-state local spontaneous functional activity in irritable bowel syndrome patients: A meta-analysis

Background: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. The current understanding of the pathogenesis underlying IBS is still unclear. Numerous studies have reported local abnormal resting state spontaneous functional activity in IBS patients in widespread brain regions. However, the results have not yet yielded consistent conclusions. Thus, we investigated common spontaneous functional activity abnormalities in patients with IBS by conducting a voxel-based meta-analysis.Methods: Up to December 2021, we performed a systematic search of IBS studies in five databases. These studies investigated the differences of resting state spontaneous brain activity between patients with IBS and healthy controls (HCs). The reference lists of included studies, relevant reviews and meta-analyses were investigated manually. Anisotropic effect-size signed differential mapping (AES-SDM) was applied in this meta-analysis.Results: Twelve studies encompassing 335 patients with IBS and 327 HCs were included in this meta-analysis. The local brain activities of the left calcarine fissure and surrounding cortex, right postcentral gyrus, left postcentral gyrus, left cerebellum, left inferior temporal gyrus, and left inferior frontal gyrus of triangular part in IBS patients were significantly increased compared with HCs, while the brain activities of the left anterior cingulate and paracingulate gyrus, right middle frontal gyrus, right supramarginal gyrus, left middle frontal gyrus, left precuneus, right putamen and right insula were significantly decreased compared with HCs.Conclusion: The current study expands on a growing literature exploring resting state activity in IBS, which provides useful insights for understanding the underlying pathophysiology of nonorganic functional bowel disease and developing more targeted treatment and intervention strategies.

Identify aberrant white matter microstructure in ASD, ADHD and other neurodevelopmental disorders: A meta-analysis of diffusion tensor imaging studies

BackgroundNeurodevelopmental disorders (NDDs) usually present overlapping symptoms. Abnormal white matter (WM) microstructure has been found in these disorders. Identification of common and unique neural abnormalities across NDDs could provide further insight into the underlying pathophysiological mechanisms. MethodsWe performed a voxel-based meta-analysis of whole-brain diffusion tensor imaging (DTI) studies in autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and other NDDs. A systematic literature search was conducted through March 2020 to identify studies that compared measures of WM microstructure between patients with NDDs and neurotypical controls. Peak voxel coordinates were meta-analyzed via anisotropic effect size-signed differential mapping (AES-SDM) as well as activation likelihood estimation (ALE). ResultsOur final sample included a total of 4137 subjects from 66 studies across five NDDs. Fractional anisotropy (FA) reductions were found in the splenium of the CC in ADHD, and the genu and splenium of CC in ASD. And mean diffusivity (MD) increases were shown in posterior thalamic radiation in ASD. No consistent abnormalities were detected in specific learning disorder, motor disorder or communication disorder. Significant differences between child/adolescent and adult patients were found within the CC across NDDs, reflective of aberrant neurodevelopmental processes in NDDs. ConclusionsThe current study demonstrated atypical WM patterns in ASD, ADHD and other NDDs. Microstructural abnormalities in the splenium of the CC were possibly shared among ASD and ADHD.

Microstructural Abnormalities of White Matter Across Tourette Syndrome: A Voxel-Based Meta-Analysis of Fractional Anisotropy

Introduction: Tourette syndrome (TS) is a neuropsychiatric disorder with multiple motor and vocal tics whose neural basis remains unclear. Diffusion tensor imaging (DTI) studies have demonstrated white matter microstructural alternations in TS, but the findings are inconclusive. In this study, we aimed to elucidate the most consistent white matter deficits in patients with TS.Method: By systematically searching online databases up to December 2020 for all DTI studies comparing fractional anisotropy (FA) between patients with TS and healthy controls (HCs), we conducted anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis to investigate FA differences in TS, as well as performed meta-regression analysis to explore the effects of demographics and clinical characteristics on white matter abnormalities among TS.Results: A total of eight datasets including 168 patients with TS and 163 HCs were identified. We found that TS patients showed robustly decreased FA in the corpus callosum (CC) and right inferior longitudinal fasciculus (ILF) compared with HCs. These two regions preserved significance in the sensitivity analysis. No regions of increased FA were reported. Meta-regression analysis revealed that age, sex, tic severity, or illness duration of patients with TS were not linearly correlated with decreased FA.Conclusion: Patients with TS display deficits of white matter microstructure in the CC and right ILF known to be important for interhemispheric connections as well as long association fiber bundles within one hemisphere. Because the results reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in TS.

Gray matter structures associated with neuroticism: A meta-analysis of whole-brain voxel-based morphometry studies.

Neuroticism is major higher‐order personality trait and has been robustly associated with mental and physical health outcomes. Although a growing body of studies have identified neurostructural markers of neuroticism, the results remained highly inconsistent. To characterize robust associations between neuroticism and variations in gray matter (GM) structures, the present meta‐analysis investigated the concurrence across voxel‐based morphometry (VBM) studies using the anisotropic effect size signed differential mapping (AES‐SDM). A total of 13 studies comprising 2,278 healthy subjects (1,275 females, 29.20 ± 14.17 years old) were included. Our analysis revealed that neuroticism was consistently associated with the GM structure of a cluster spanning the bilateral dorsal anterior cingulate cortex and extending to the adjacent medial prefrontal cortex (dACC/mPFC). Meta‐regression analyses indicated that the neuroticism‐GM associations were not confounded by age and gender. Overall, our study is the first whole‐brain meta‐analysis exploring the brain structural correlates of neuroticism, and the findings may have implications for the intervention of high‐neuroticism individuals, who are at risk of mental disorders, by targeting the dACC/mPFC.

Chemotherapy-induced grey matter abnormalities in cancer survivors: a voxel-wise neuroimaging meta-analysis.

Findings regarding chemotherapy-induced grey matter abnormalities are heterogeneous, and no meta-analysis has quantitatively assessed brain structural alterations in cancer survivors treated with chemotherapy. To investigate the grey matter abnormalities in non-CNS (central nervous system) cancer survivors treated with chemotherapy using Anisotropic Effect Size Signed Differential Mapping (AES-SDM) software. We identified studies published up to Sep 2018 that compared grey matter in non-CNS cancer survivors treated with chemotherapy (CT+, 10 data sets including 433 individuals) and cancer survivors not treated with chemotherapy (CT-, 7 data sets including 210 individuals) or healthy controls (HC, 3 data sets including 407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Compared with both CT- and HC, the CT + groups exhibited a reduced grey matter volume (GMV), mainly in the prefrontal and anterior cingulate cortex (ACC) and right fusiform gyrus (FG). A smaller GMV in the FG and prefrontal cortex were found in the CT + compared with the CT-groups and in the CT + groups with impaired cognition. GMV in two areas was positively associated with the time since chemotherapy. The present results suggest that non-CNS cancer survivors treated with chemotherapy exhibit grey matter abnormalities in the brain, especially in the prefrontal and ACC cortex. Grey matter volume changes after chemotherapy may contribute to cognitive impairments in cancer survivors that can be observed after chemotherapy.

Altered white matter microarchitecture in Parkinson's disease: a voxel-based meta-analysis of diffusion tensor imaging studies.

This study aimed to define the most consistent white matter microarchitecture pattern in Parkinson's disease (PD) reflected by fractional anisotropy (FA), addressing clinical profiles and methodology-related heterogeneity. Web-based publication databases were searched to conduct a meta-analysis of whole-brain diffusion tensor imaging studies comparing PD with healthy controls (HC) using the anisotropic effect size-signed differential mapping. A total of 808 patients with PD and 760 HC coming from 27 databases were finally included. Subgroup analyses were conducted considering heterogeneity with respect to medication status, disease stage, analysis methods, and the number of diffusion directions in acquisition. Compared with HC, patients with PD had decreased FA in the left middle cerebellar peduncle, corpus callosum (CC), left inferior fronto-occipital fasciculus, and right inferior longitudinal fasciculus. Most of the main results remained unchanged in subgroup meta-analyses of medicated patients, early stage patients, voxel-based analysis, and acquisition with 30 diffusion directions. The subgroup meta-analysis of medication-free patients showed FA decrease in the right olfactory cortex. The cerebellum and CC, associated with typical motor impairment, showed the most consistent FA decreases in PD. Medication status, analysis approaches, and the number of diffusion directions have an important impact on the findings, needing careful evaluation in future meta-analyses.

<p>Pleiotropic action of genetic variation in ZNF804A on brain structure: a meta-analysis of magnetic resonance imaging studies</p>

ObjectiveThe zinc finger protein 804A (ZNF804A) gene encodes the protein 804A containing the C2H2 zinc finger structure, which plays an important role in embryonic nerve development and repair. Previous studies have shown a significant association between the ZNF804A genetic variation polymorphism rs1344706 and the risk of schizophrenia and brain structure abnormalities. However, the findings are inconsistent.Materials and methodsSeventeen studies on structural magnetic resonance imaging (sMRI), with 1,031 schizophrenia patients and 3,416 healthy controls, were included in the meta-analysis. These analyses were performed using Anisotropic Effect-Size Signed Differential Mapping (AES-SDM) software and Comprehensive Meta-Analysis (CMA) software.Resultsrs1344706 risk allele carriers of schizophrenia had increased gray matter in the brain regions including frontal lobe, temporal lobe, and other brain regions, but the carriers of healthy individuals had decreased gray matter and white matter integrity in the frontal lobe, central network, and other brain regions. The results of sensitivity analysis are stable, but publication bias exists in a few analyses of indexes.ConclusionAbnormalities of brain structure have a strong relationship with ZNF804A gene rs1344706 polymorphism, but the association may be different in healthy individuals and those with mental disorders.

Brain regions responding to acupuncture stimulation of Zusanli (ST36) in healthy subjects analyzed on the basis of spontaneous brain activity

To determine the attributes of responses of the higher nerve center to acupuncture stimulation of Zusanli (ST36) on the basis of spontaneous brain activity, so as to explore the synchronization level of different brain rejoins after acupuncture. All studies using fMRI to investigate the effect of acupuncture stimulation of ST36 and/or other acupoints on the human brain (at least 10 healthy subjects or patients in one group) published in journals from January of 1995 to January of 2018 were searched from databases of CNKI and PubMed by using keywords of acupuncture, electroacupuncture, and resting-state functional magnetic resonance images (rs-fMRI) or regional homogeneity (ReHo). Brain functional image data of acupuncture stimulation of ST36 and/or other acupoints were collected and analyzed with anisotropic effect size-signed differential mapping (AES-SDM) software (Meta-analysis), and those of acupuncture of simple ST36 analyzed as a subgroup. A total of 229 papers in Chinese and 109 in English were collected. According to our inclusive and exclusive standards, 11 papers containing 235 subjects were brought into analysis at last. Meta-analysis of brain image data of acupuncture at ST36 and/or other acupoints (comparison between pre- and post-acupuncture) revealed that the same brain regions (generality) which showed a significant increase in ReHo, are the right and left anterior cingulated gyrus, right caudate, left superior frontal gyrus, right middle frontal gyrus, and the right paracentral lobe, and those which showed a marked decrease of ReHo are the left mid-inferior occipital gyrus, left and right precentral and postcentral gyrus. The brain regions responding to acupuncture at ST36 only (specificity) are the right inferior parietal lobe, left middle inferior gyrus, right posterior lobe of cerebellum, and the left angular gyrus which displayed an increase of ReHo, and the right middle superior frontal gyrus which showed a decrease in ReHo. After acupuncturing at ST36, the relative generality and specificity of the central response in healthy subjects reflected as the location of the affected brain regions and the difference in the synchronization level of the corresponding spontaneous brain activities.

Altered white matter microarchitecture in amyotrophic lateral sclerosis: A voxel-based meta-analysis of diffusion tensor imaging.

BackgroundThe results of recent diffusion tensor imaging (DTI) studies on amyotrophic lateral sclerosis (ALS) are inconclusive and controversial. We performed a voxel-based meta-analysis to identify a statistical consensus among published DTI studies of altered white matter (WM) microarchitecture in ALS.MethodsA systematic search was conducted for relevant studies that used voxel-wise analyses of WM microarchitecture in patients with ALS. Anisotropic effect size-signed differential mapping (AES-SDM) was applied to analyze fractional anisotropy (FA) differences between ALS patients and healthy controls. Meta-regression analysis was used to explore the effects of clinical characteristics on WM integrity in patients with ALS.ResultsA total of 14 studies with 16 datasets that included 396 patients and 360 healthy controls were identified. The pooled meta-analysis revealed that patients with ALS exhibited significant FA reductions in two clusters relative to healthy controls. The largest cluster exhibited a peak coordinate in the left corona radiata, extending to the body and splenium of the corpus callosum, left superior longitudinal fasciculus, posterior limb of the internal capsule, right corona radiata, and bilateral cingulate gyrus. The other cluster exhibited decreased FA in the right corticospinal tract that extended to the right cerebral peduncle. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score was positively correlated with the FA reduction in the left corona radiata. Mean age and illness duration were not linearly correlated with the FA reductions.ConclusionsThis study provides a thorough profile of WM microarchitecture alterations in patients with ALS and further evidence that the neuronal degeneration is not limited to the corticospinal tract but also includes extra-motor areas, which supports the view that ALS is a multisystem degenerative disorder that involves the white matter.

Microstructural brain abnormalities in medication-free patients with major depressive disorder: a systematic review and meta-analysis of diffusion tensor imaging

Multiple meta-analyses of diffusion tensor imaging (DTI) studies have reported impaired white matter integrity in patients with major depressive disorder (MDD). However, owing to inclusion of medicated patients in these studies, it is difficult to conclude whether these reported alterations are associated with MDD or confounded by medication effects. A meta-analysis of DTI studies on medication-free (medication-naive and medication washout) patients with MDD would therefore be necessary to disentangle MDD-specific effects. We analyzed white matter alterations between medication-free patients with MDD and healthy controls using anisotropic effect size-signed differential mapping (AES-SDM). We used DTI query software for fibre tracking. Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy (FA) reductions in white matter of the right cerebellum hemispheric lobule, body of the corpus callosum (CC) and bilateral superior longitudinal fasciculus III (SLF III), whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients. Fibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts, body of the CC, bilateral SLF III and arcuate fascicle. The analytic techniques, patient characteristics and clinical variables of the included studies were heterogeneous; we could not exclude the effects of nondrug therapies owing to a lack of data. By excluding the confounding influences of current medication status, findings from the present study may provide a better understanding of the underlying neuropathology of MDD.

Disorganization of white matter architecture in major depressive disorder: a meta-analysis of diffusion tensor imaging with tract-based spatial statistics

White matter (WM) abnormalities have long been suspected in major depressive disorder (MDD). Tract-based spatial statistics (TBSS) studies have detected abnormalities in fractional anisotropy (FA) in MDD, but the available evidence has been inconsistent. We performed a quantitative meta-analysis of TBSS studies contrasting MDD patients with healthy control subjects (HCS). A total of 17 studies with 18 datasets that included 641 MDD patients and 581 HCS were identified. Anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis was performed to assess FA alterations in MDD patients compared to HCS. FA reductions were identified in the genu of the corpus callosum (CC) extending to the body of the CC and left anterior limb of the internal capsule (ALIC) in MDD patients relative to HCS. Descriptive analysis of quartiles, sensitivity analysis and subgroup analysis further confirmed these findings. Meta-regression analysis revealed that individuals with more severe MDD were significantly more likely to have FA reductions in the genu of the CC. This study provides a thorough profile of WM abnormalities in MDD and evidence that interhemispheric connections and frontal-striatal-thalamic pathways are the most convergent circuits affected in MDD.

Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis.

Childhood maltreatment acts as a severe stressor that produces a cascade of physiological and neurobiological changes that lead to enduring alterations in brain structure. However, structural neuroimaging findings have been inconsistent. The authors conducted a meta-analysis of published whole-brain voxel-based morphometry studies in childhood maltreatment to elucidate the most robust volumetric gray matter abnormalities relative to comparison subjects to date. Twelve data sets were included, comprising 331 individuals (56 children/adolescents and 275 adults) with a history of childhood maltreatment and 362 comparison subjects (56 children/adolescents and 306 adults). Anisotropic effect size-signed differential mapping, a voxel-based meta-analytic method, was used to examine regions of smaller and larger gray matter volumes in maltreated individuals relative to comparison subjects. Relative to comparison subjects, individuals exposed to childhood maltreatment exhibited significantly smaller gray matter volumes in the right orbitofrontal/superior temporal gyrus extending to the amygdala, insula, and parahippocampal and middle temporal gyri and in the left inferior frontal and postcentral gyri. They had larger gray matter volumes in the right superior frontal and left middle occipital gyri. Deficits in the right orbitofrontal-temporal-limbic and left inferior frontal regions remained in a subgroup analysis of unmedicated participants. Abnormalities in the left postcentral and middle occipital gyri were found only in older maltreated individuals relative to age-matched comparison subjects. The findings demonstrate that the most consistent gray matter abnormalities in individuals exposed to childhood maltreatment are in relatively late-developing ventrolateral prefrontal-limbic-temporal regions that are known to mediate late-developing functions of affect and cognitive control, which are typically compromised in this population.